This short article is dedicated to Professor Edwin Haslam, an inspiration to us all !

A short answer to this title question would be that polyphenols occupy today a unique place in science as the only class of bioactive natural products that the general public has certainly heard about as a consequence of their presence in fruit-, seed- and vegetable-derived food and beverages and of their implication in the formulation of well-marketed cosmetic and parapharmaceutical products. Such an answer undoubtedly deserves a more detailed argumentation for the benefit of some of you among scientists not yet aware of the significance of polyphenols in science. To do so in the most concise and still comprehensive manner possible, I have to include in my arguments the answer to another and more basic question! What exactly are polyphenols? The answer is in fact not as trivial as one might think, and my intent, through this article, is to propose a definition that should clear up most common misconceptions about these naturally occurring substances. I do anticipate some criticisms, but shall remain open to further discussions and sound amendments to my proposal. In any event, we should first put some historical perspective into any attempt to come up with a definition of polyphenols. We obviously are not the first scientists to get interested in polyphenols research… About fifty years ago, Theodore White proposed a first definition based on the ancestral and still today applied utilisation of polyphenolic substances of vegetable origin in the conversion of animal skins into leather. This empiric classification of plant polyphenols as molecules having a “tanning” action led to their referring in the early literature to as “vegetable tannins”. Considerable efforts had been devoted during the first half of the past century to the study of the chemistry of tanning plant extracts in attempts to tackle the structural characterization of their polyphenolic constituents. But even the tenacity and major contributions of the Nobel Laureate Emil Fischer and those of several of his disciples, such as Karl Freudenberg, only unveiled the complexity of the problem and felt short of placing polyphenol research as a priority theme in chemistry. The lack of more advanced technological tools at the time is certainly to be incriminated for this early days shortfall of deeper knowledge of complex polyphenols at the molecular level and, consequently, for the absence of their recognition by the chemists community. In fact, this deplorable situation is still in some respects unchanged today as the study of plant polyphenols remains a special and rather exotic topic in modern organic chemistry. Complexity can unfortunately be the source of rebuttal to scientific exploration, and any bad reputation is always difficult to erase…

Fortunately, botanists, plant physiologists and biochemists, as well as a few obstinate chemists kept on underlying the crucial role played by polyphenols, not only in their respective domain of basic research, but also in broader areas of general public interest such as medicine, nutrition, agriculture, ecology, not forgetting industrial chemistry. Let’s agree to give credit to three scientists who managed during the second half of the past century to go many steps further toward our basic knowledge of plant polyphenols. The first two are biochemists, E. C. Bate-Smith and Tony Swain, who carried out numerous and seminal investigations on plant phenolics that had tremendous impacts on the development of polyphenol research and its appreciation by the scientific community at large. They came up with a simple definition of polyphenols that was still mainly based on experimental observations made on the physico-chemical behavior of plant phenolics capable of expressing a tanning action. This definition was later refined at the molecular level by the third scientist to whom we should give credit for his outstanding achievements in the field. I am of course referring to Edwin Haslam, physical organic chemist who, until his recent retirement, dedicated his career to the study of many if not all aspects of polyphenol science, including chemical reactivity and synthesis, phytochemical, biochemical and biophysical aspects of various classes of polyphenols in their interactions with other biomolecules such as polysaccharides and proteins. As alluded to above, Haslam proposed a first comprehensive definition of plant polyphenols based on the earlier proposals of Bate-Smith, Swain and White, which includes specific structural characteristics common to all phenolics having a tanning property. We could thus refer to it as the White–Bate-Smith–Swain–Haslam (WBSSH) definition. It implies that the term “polyphenol” (syn. vegetable tannin) should be exclusively attributed to water-soluble phenolic compounds having molecular masses between 500 to 3000-4000 Da, possessing 12 to 16 phenolic hydroxyl groups and five to seven aromatic rings per 1000 relative molecular mass, giving the usual phenolic reactions such as the formation of intense blue-black complexes upon treatment with iron(III) salts, and expressing special properties such as the ability to precipitate alkaloids and proteins. This definition can perhaps be subjected to criticisms because of its apparent narrow-minded view, but its interpretation leads to the conclusion that only substances bearing a large enough number of di- and trihydroxyphenyl units, either because of their oligomeric structure or because of the specificity of their structural architecture, can fit the definition as long as they remain soluble in water. This would mean, for example, that hydroxyphenylpropanoid-based lignin polymers are not “polyphenols”! Indeed, only three classes of polyhydroxyphenyl-bearing natural products known today can first pretend to respond to the restrictions implied by the WBSSH definition. These substances are (1) the proanthocyanidins (syn. condensed tannins) such as procyanidins, prodelphinidins and profisetinidins that are derived from the oligomerization of flavan-3-ol units such as catechin, epicatechin, epigallocatechin and fisetinidol through condensation and/or oxidation reactions, (2) the gallo- and ellagitannins (syn. hydrolysable tannins) that are derived from the metabolism of the shikimate-derived gallic acid (i.e., 3,4,5-trihydroxybenzoic acid), which leads via esterification and phenolic oxidative coupling reactions to a myriad (> 500) of polyphenolic ester derivatives of sugar-type polyols, mainly glucose, and (3) the phlorotannins that are found in brown algae and derived from the oxidative coupling of phloroglucinol (i.e., 1,3,5-trihydroxybenzene). To these first three classes of substances could be added other more or less complex phenolic substances that may also fit this definition of tanning polyphenols, as we shall see below.

That said, we have anyway to admit that the original WBSSH definition of “polyphenols” has considerably broadened out over the years to include today many much simpler phenolic structures. This is perhaps a consequence of the general recognition of plant phenolics at large as biologically active substances. Herbs, spices and various plant extracts, rich in phenolic compounds, have been used for thousands of years in traditional medicines all over the world. The literature now abounds in reports on the identification of phenolic entities as active principles of these alternative medications. The regular intake of fruits and vegetables is today highly recommended in the human diet, mainly because the “polyphenols” they contain are thought to play important roles in long term health and reduction in the risk of chronic and degenerative diseases. Furthermore, this increasing recognition of the benefits brought by plant phenols and polyphenols to human health has sparked a new appraisal of various plant-derived food and beverages, such as olive oil, all kinds of fruit juices, chocolate, coffee, tea, and even alcoholic beverages such as wine and cider. Their content in phenolic substances has fuelled numerous investigations that, again, unveiled the therapeutic potential of these natural products, even though their bioavailability in the human body is still a fiercely debated question.

A large number of these plant phenolics found in food and beverages are small molecules with no tanning action, but their chemistry can lead to more complex substances with tannin-like properties. They encompass several classes of structurally-diverse entities that are essentially all biogenerated through either the shikimate/phenylpropanoid (Þ C6-C3) or the “polyketide” acetate/malonate (Þ C6) secondary metabolic pathway, or both. On the top of the list are such metabolic hybrids, the flavonoids (C6-C3-C6), which include inter alia flavones (e.g., apigenin), flavanones (e.g. naringenin), flavonols (e.g. quercetin), flavanols (e.g. catechin), isoflavones (e.g. genistein), anthocyanidins (e.g. malvidin), chalcones (e.g. butein), aurones (e.g. aureusidin) and xanthones (C6-C1-C6, e.g. garcilivin A). Some members of this huge class of natural products (> 8000 structures !), usually bearing two mono- to trihydroxyphenyl units, can serve as precursors to oligo- and polymeric phenolic systems. It is, for example, the case of the flavanols that not only lead to the proanthocyanidins (vide supra), but also, through oxidative transformations, to the tropolone-containing dimeric theaflavins and complex polymeric thearubigins of black tea (syn. theatannins). The general phenylpropanoid metabolism furnishes a series of hydroxycinnamic acids (C6-C3) differing from one another by the number of hydroxy and methoxy groups on their phenyl unit (i.e. 4-hydroxycinnamic acid, ferulic acid, sinapic acid, caffeic acid). These monophenolic carboxylic acids are often found esterified to polyols. One of them, for example, caffeic acid (i.e. 3,4-dihydroxycinnamic acid), is encountered in medium-sized polyester derivatives of the tetraolic quinic acid found in coffee beans. These derivatives are known as the chlorogenic acids (syn. caffetannins). In fact, numerous polyols, including saccharides, are found acylated, in much the same way as in the hydrolysable gallotannins, by polyhydroxyphenylcarbonoyl residues, among which the most common units are the caffeoyl (C6-C3), the galloyl (C6-C1) and its dehydrodimeric hexahydroxybiphenoyl (C6-C1)2 units. A last illustrating example of such polyphenolic compounds is the so-called hamamelitannin composed of two gallic acids esterified to the rare sugar hamamelose and found in significant quantities in the bark of the witch hazel (Hamamelis virginiana), oak and chestnut trees. Through hydration, esterification and phenolic oxidative coupling reactions, caffeic acid also gives rise to oligomeric structures, such as the dimeric rosmarinic acid, up to tetramers, such as rabdosiin, originally found in Labiatae plant species (syn. labiatetannins). The phenylpropanoid/acetate hybrid metabolic pathway leads to another important class of phenolic substances, the polyhydroxystilbenes (C6-C2-C6). The most famous example is unarguably the phytoalexin trans-resveratrol (i.e., 3,5,4’-trihydroxy-trans-stilbene), which has been the center of much scientific attention and mediatic exposure following its biological evaluation as a cancer chemopreventing agent and its detection in red wine (ca. 1-6 mg/L). Such phenolic systems featuring a conjugated carbon–carbon bond in their side-chains are particularly prone to undergo oligomerization events via coupling of delocalized phenoxy radicals generated by one-electron oxidation reactions. Much like the hydroxycinnamic acids, esters and alcohols that are converted into lignan/neolignan dimers (C6-C3)2 and plant cell wall lignin polymers (C6-C3)n by such oxidative coupling processes, resveratrol and its hydroxystilbenoid analogues can react in the same manner to furnish polyphenolic oligomers.

The above compendium of plant phenolics found in food and beverages, as well as in traditional medicines, is far from being exhaustive, and should at least be completed, for the sake of this discussion, by numerous monophenolic compounds of various biochemical and chemical origins. In this vein, cinnamic acid and its hydroxylated derivatives (C6-C3) also occupy a special place, for their metabolism leads to several additional monophenolics through inter alia decarboxylation, dehydration, hydrogenation, aromatic hydroxylation, oxidative cleavage and cyclization reactions. Again, It is not possible to give herein an exhaustive list of these compounds, but a few illustrating examples could be worth mentioning, since the study of their chemical, biological and organoleptic properties is generally included in current polyphenol research topics. One can, for example, cite the aldehydic vanillin (C6-C1), the characteristic aroma of fermented vanilla beans; the carboxylic salicylic acid (C6-C1), an important agent in plant defence mechanisms (; the catecholic hydroxytyrosol (C6-C2), a powerful antioxidant extracted from olive oil mill wastewaters; eugenol (C6-C3), the main aroma of ripped banana also found in cloves from which it is extracted at the industrial scale; scopoletin (C6-C3), an example of hydroxycoumarins expressing various biological activities, including a phytoallexin-like antimicrobial action in plants; the polyketide juglone (C6-C4), an allelopathic naphthoquinone also responsible for the colour darkening of walnuts upon maturation; the shikimate/isoprenoid a-tocopherol (i.e. vitamin E), an essential lipophilic antioxydant of the human diet…

This entanglement of structure types is admittedly far from providing a clear picture of the plant polyphenols family. For sure, the presence of more than one hydroxyl group on a benzene ring or other arene systems does not make them “polyphenols”. Catechol, resorcinol, pyrogallol, and phloroglucinol, all di- and trihydroxylated benzene (C6) derivatives, are still defined as “phenols” according to the IUPAC official nomenclature rules of chemical compounds. Many such monophenolics are often quoted as “polyphenols” by the cosmetic and parapharmaceutic industries, but they cannot be by any scientifically-accepted definition. Hydroxytyrosol (i.e. 3,4-dihydroxyphenylethanol) is one flagrant example suffering from such an abuse. The meaning of the chemical term “phenol” includes both the arene ring and its hydroxyl substituent(s). Hence, even if we agree to include in a definition polyphenolic structures with no tanning action, the term “polyphenol” should be restricted, in a strict chemical sense, to structures bearing at least two phenolic moieties independently of the number of hydroxyl groups they each bear. But this definition needs additional restrictions, for many natural products of various biosynthetic origins do contain more than one phenolic unit. It is, for example, the case for many alkaloids derived from the phenylalanine/tyrosine amino acids. The natural occurrence of such alkaloids then gives us a poser in any attempts to propose a definition of polyphenols strickly based on biosynthetic origin(s) grounds, for these amino acids themselves are primary metabolites of the shikimate/phenylpropanoid pathway. So, here is my proposal! The term “polyphenol” should be used to define compounds exclusively derived from the shikimate/phenylpropanoid and/or the polyketide pathway, featuring more than one phenolic unit and deprived of nitrogen-based functions. This definition lets out all monophenolic structures, as well as all their naturally occurring derivatives such as phenyl esters, methyl phenyl ethers and O-phenyl glycosides. However, investigations on these compounds, which are often the biogenetic precursors of “true” polyphenols, definitely have their place in polyphenol research, but qualifying them as polyphenols is pushing it too far.

The inclusion of monophenolic compounds in polyphenol-oriented research can perhaps find its justification through an important property that all phenols share to some extent, and that is their capability to scavenge oxidatively-generated free radicals such as those derived from lipids and nucleic acids. This antioxidant activity of phenols is frequently cited to be the main event responsible for the prevention of age-related diseases such as neurodegeneration, carcinogenesis and cardiovascular diseases, including atherosclerosis, by phenol/polyphenol-rich diets. As a consequence of such a potential for protective therapies, antioxidation has become the trademark of plant phenolics in their utilisation in cosmetic and parapharmaceutic products. Caution is warranted, however, for some phenoxy radicals generated through homolytic hydrogen atom abstraction and/or one-electron oxidative quenching of free radicals could be further transformed into electrophilic (toxic?) quinone derivatives, if they escape the redox cycle.

Besides this general mode of action based on the chemical reactivity inherent to the phenol function, simple phenols and certain polyphenols can also physically and specifically interact with biomolecules, including therapeutically significant enzymes. In this context, it is worth recalling that phenols are amphiphilic entities capable of mimicking the physico-chemical behavior of polar aromatic amino acids such as tyrosine, which is often found as a key residue in functional proteins. Such considerations raise some intriguing and fascinating questions. Why did nature install a hydroxyl group on the amino acid phenylalanine? Why did plants choose to produce phenolic secondary metabolites? As a chemical defence against pathogens and herbivores? Probably so, among many other beneficial properties that plants can exploit from their (poly)phenolic metabolites for their growth, reproduction, resistance and protection against their environment. It is then somewhat surprising to realize that plant polyphenols have been mostly left out of medicinal drug developments. The reasons of this relative disapproval of polyphenols by the pharmaceutical industry are unclear, but medicinal chemists might have been influenced by the earlier considerations of plant “tanning” polyphenols as structurally rather undefined and water-soluble oligomers only capable of forming complexes with alkaloids and proteins and of chelating metallic ions in non-specific manners. These considerations might be indeed justified for some polyphenols such as the gallotannins causing the precipitation of collagen during tanning processes, or the proanthocyanidins interacting with salivary proteins to exhibit the perception of astringency upon tasting red wines. Hence, standard industrial extraction protocols of plant secondary metabolites usually involve a step to ensure the complete passage of all polyphenolic compounds in aqueous extracts in order to avoid “false-positive” results in screening against a given biomolecular target. Some of us are of the opinion that a closer look at these put-aside aqueous extracts should be worth it, for they may contain some polyphenolic “magic bullets”, or at least interesting lead compounds for pharmaceutical drug developments. Fortunately, the situation is slowly changing, as we can infer from the increasing number of academic reports from non “polyphenolists” demonstrating the value of the unique structural features of these natural products. Polyphenol research will undoubtedly continue to expand its domains of investigation and could be in route to some even more exciting time in the pharmaceutical drug development arena!

I would like to end this article by a short anecdote that will perhaps contribute to convince the most sceptical scientists among you of the value of polyphenols. In 1934, Désiré Cordier (1858-1940), founder of the world famous Cordier wine trading house, organized the first “longevity festival” in Saint-Julien-Beychevelle (Médoc, France), after having noted that life expectancy in this wine-producing area near Bordeaux was 45% higher than the national average. All the centenarians from Médoc came to celebrate wine as the “elixir of life”… A votre santé !